This invention relates to the novel processes for the preparation of 9,11-epoxy steroid compounds, especially those of the 20-spiroxane series and their analogs, novel intermediates useful in the preparation of steroid compounds, and processes for the preparation of such novel intermediates. Most particularly, the invention is directed to novel and advantageous methods for the preparation of methyl hydrogen 9,11xcex1-epoxy-17xcex1-hydroxy-3-oxopregn-4-ene-7xcex1,21-dicarboxylate, xcex3-lactone (eplerenone; epoxymexrenone).
Methods for the preparation of 20-spiroxane series compounds are described in U.S. Pat. No. 4,559,332. The compounds produced in accordance with the process of the ""332 patent have an open oxygen containing ring E of the general formula: 
in which
xe2x80x94Axe2x80x94Axe2x80x94 represents the group xe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94,
R1 represents an xcex1-oriented lower alkoxycarbonyl or hydroxycarbonyl radical.
xe2x80x94Bxe2x80x94Bxe2x80x94 represents the group xe2x80x94CH2xe2x80x94CH2xe2x80x94 or an xcex1- or xcex2-oriented group 
R6 and R7 being hydrogen
X represents two hydrogen atoms or oxo,
Y1 and y2 together represent the oxygen bridge xe2x80x94Oxe2x80x94, or
Y1 represents hydroxy, and
Y2 represents hydroxy, lower alkoxy or, if X represents H2, also lower alkanoyloxy,
and salts of such compounds in which X represents oxo and Y2 represents hydroxy, that is to say of corresponding 17xcex2-hydroxy-21-carboxylic acids.
U.S. Pat. No. 4,559,332 describes a number of methods for the preparation of epoxymexrenone and related compounds of Formula IA. The advent of new and expanded clinical uses for epoxymexrenone create a need for improved processes for the manufacture of this and other related steroids.
The primary object of the present invention is the provision of improved processes for the preparation of epoxymexrenone, other 20-spiroxanes and other steroids having common structural features. Among the particular objects of the invention are: to provide an improved process that produces products of Formula IA and other related compounds in high yield; the provision of such a process which involves a minimum of isolation steps; and the provision of such a process which may be implemented with reasonable capital expense and operated at reasonable conversion cost.
Accordingly, the present invention is directed to a series of synthesis schemes for epoxymexrenone; intermediates useful in the manufacture of eplerenone; and syntheses for such novel intermediates.
The novel synthesis schemes are described in detail in the Description of Preferred Embodiments. Among the novel intermediates of this invention are those described immediately below.
A compound of Formula IV corresponds to the structure: 
wherein:
xe2x80x94Axe2x80x94Axe2x80x94 represents the group xe2x80x94CHR4xe2x80x94CHR5xe2x80x94 or xe2x80x94CR4xe2x95x90CR5xe2x80x94
R3, R4 and R5 are independently selected from the group consisting of hydrogen, halo, hydroxy, lower alkyl, lower alkoxy, hydroxyalkyl, alkoxyalkyl, hydroxy carbonyl, cyano, aryloxy,
R1 represents an alpha-oriented lower alkoxycarbonyl or hydroxycarbonyl radical,
R2 is an 11xcex1- leaving group the abstraction of which is effective for generating a double bond between the 9- and 11-carbon atoms;
xe2x80x94Bxe2x80x94Bxe2x80x94 represents the group xe2x80x94CHR6xe2x80x94CHR7xe2x80x94 or an alpha- or beta-oriented group: 
xe2x80x83where R6 and R7 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, and
R8 and R9 are independently selected from the group consisting of hydrogen, halo, lower alkoxy, acyl, hydroxalkyl, alkoxyalkyl, hydroxycarbonyl, alkyl, alkoxycarbonyl, acyloxyalkyl, cyano, aryloxy, or R8 and R9 together comprise a carbocyclic or heterocyclic ring structure, or R8 or R9 together with R6 or R7 comprise a carbocyclic or heterocyclic ring structure fused to the pentacyclic D ring.
A compound of Formula IVA corresponds to Formula IV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula IVB corresponds to Formula IVA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae IVC, IVD and IVE, respectively, correspond to any of Formula IV, IVA, or IVB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, R3 is hydrogen, and R1 is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula IV may be prepared by reacting a lower alkylsulfonylating or acylating reagent, or a halide generating agent, with a corresponding compound within the scope of Formula V.
A compound of Formula V corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R1, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VA corresponds to Formula V wherein R8 and R9 with the ring carbon to which they are attached together form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VB corresponds to Formula VA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VC, VD and VE, respectively, correspond to any of Formula V, VA, or VB
wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, R3 is hydrogen, and R1 is alkoxycarbonyl, preferably methoxycarbonyl. Compounds within the scope of Formula V may be prepared by reacting an alkali metal alkoxide with a corresponding compound of Formula VI.
A compound of Formula VI corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VIA corresponds to Formula VI wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VIB corresponds to Formula VIA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VIC, VID and VIE, respectively, correspond to any of Formula VI, VIA, or VIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds of Formula VI, VIA, VIB and VIC are prepared by hydrolyzing a compound corresponding to Formula VII, VIIA, VIIB or VIIC, respectively.
A compound of Formula VII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VIIA corresponds to Formula VII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VIIB corresponds to Formula VIIA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VIIC, VIID and VIIE, respectively, correspond to any of Formula VII, VIIA, or VIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. A compound within the scope of Formula VII may be prepared by cyanidation of a compound within the scope of Formula VIII.
A compound of Formula VIII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula VIIIA corresponds to Formula VIII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula VIIIB corresponds to Formula VIIIA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae VIIIC, VIIID and VIIIE, respectively, correspond to any of Formula VIII, VIIIA, or VIIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula VIII are prepared by oxidizing a substrate comprising a compound of Formula XXX as described hereinbelow by fermentation effective for introducing an 11-hydroxy group into the substrate in xcex1-orientation.
A compound of Formula XIV corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XIVA corresponds to Formula XIV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XIV corresponds to Formula XIVA wherein R8 and R9 together with the ring carbon to which they are attached form the structure of Formula XXXIII: 
Compounds of Formulae XIVC, XIVD and XIVE, respectively, correspond to any of Formula XIV, XIVA, or XIVB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XIV can be prepared by hydrolysis of a corresponding compound within the scope of Formula XV.
A compound of Formula XV corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XVA corresponds to Formula XV wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XVB corresponds to Formula XVA wherein R8 and R9 together with the ring carbon to which they are attached form the structure of Formula XXXIII: 
Compounds of Formulae XVC, XVD and XVE, respectively, correspond to any of Formula XV, XVA, or XVB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XV can be prepared by cyanidation of a corresponding compound within the scope of Formula XVI.
A compound of Formula XXI corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXIA corresponds to Formula XXI wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XXIB corresponds to Formula XXIA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XXIC, XXID and XXIE, respectively, correspond to any of Formula XXI, XXIA, or XXIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXI may be prepared by hydrolyzing a corresponding compound within the scope of Formula XXII.
A compound of Formula XXII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXIIA corresponds to Formula XXII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XXIIB corresponds to Formula XXIIA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XXIIC, XXIID and XXIIE, respectively, correspond to any of Formula XXII, XXIIA, or XXIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXII May be prepared by cyanidation of a compound within the scope of Formula XXIII.
A compound of Formula XXIII corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3, R8 and R9 are as defined in Formula IV.
A compound of Formula XXIIIA corresponds to Formula XXIII wherein R8 and R9 together with the ring carbon to which they are attached form the structure: 
where X, Y1, Y2 and C(17) are as defined above.
A compound of Formula XXIIIB corresponds to Formula XXIIIA wherein R8 and R9 together form the structure of Formula XXXIII: 
Compounds of Formulae XXIIIC, XXIIID and XXIIIE, respectively, correspond to any of Formula XXIII, XXIIIA, or XXIIIB wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula XXIII can be prepared by oxidation of a compound of Formula XXIV, as described hereinbelow.
A compound of Formula 104 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, and R3 are as defined in Formula IV, and R11 is C1 to C4 alkyl.
A compound of Formula 104A corresponds to Formula 104 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 104 may be prepared by thermal decomposition of a compound of Formula 103.
A compound of Formula 103 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3 and R11 are as defined in Formula 104.
A compound of Formula 103A corresponds to Formula 103 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 103 may be prepared by reaction of a corresponding compound of Formula 102 with a dialkyl malonate in the presence of a base such as an alkali metal alkoxide.
A compound of Formula 102 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3 and R11 are as defined in Formula 104.
A compound of Formula 102A corresponds to Formula 102 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 102 may be prepared by reaction of a corresponding compound of Formula 101 with a trialkyl sulfonium compound in the presence of a base.
A compound of Formula 101 corresponds to the structure: 
wherein xe2x80x94Axe2x80x94Axe2x80x94, xe2x80x94Bxe2x80x94Bxe2x80x94, R3 and R11 are as defined in Formula 104.
A compound of Formula 101A corresponds to Formula 101 wherein each of xe2x80x94Axe2x80x94Axe2x80x94 and xe2x80x94Bxe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CH2xe2x80x94, and R3 is hydrogen. Compounds within the scope of Formula 101 may be prepared by reaction of 11xcex1-hydroxyandrostene-3,17-dione or other compound of Formula XXXVI with a trialkyl orthoformate in the presence of an acid.
Based on the disclosure of specific reaction schemes as set out hereinbelow, it will be apparent which of these compounds have the greatest utility relative to a particular reaction scheme. Use of the compounds of this invention are useful as intermediates for epoxymexrenone and other steroids.
Other objects and features will be in part apparent and in part pointed out hereinafter.